De I'URSS à la Russie : les institutions internationales de sécurité au service d'une superpuissance en chute libre

Constatant que sa puissance diminuait à vue d'oeil, la Russie, tout comme VURSS à la veille de sa dissolution, a recouru aux us afin de préserver ses prérogatives d'une grande puissance menacées par les grands bouleversements géopolitiques. L'article montre à travers trois études de cas combien VURSS durant la crise du Golfe s'efforça à grand-peine de sauvegarder ses intérêts sérieusement entamés ; expérience que la Russie connaîtra avec l'élargissement de I'OTAN vers les pays de l'Europe centrale et orientale. Seule au Conseil de sécurité la puissance grandement amoindrie de la Russie paraît être à l'abri. L'article conclut que la Russie est placée constamment dans des contraintes institutionnelles qui lui échappent malgré ses tentatives d'employer les us existantes pour arrêter l'hémorragie de son influence historique mondiale.Aware that its power was diminishing rapidly, Russia, in the same way as the Soviet Union at the eve of its dissolution, resorted to its in order to preserve its great-power prerogatives threatened as they were by major geopolitical reversals. Through three case studies, this article shows to what extent the Soviet Union during the Gulf Crisis sought with considerable difficulty to forestall the downgrading of its power; an experience repeated by Russia in the NATO enlargement issue. Only at the Security Council does Russia's power seem to be in a relatively safe place. The article concludes that Russia finds itself constantly placed under institutional constraints despite its efforts to stop the downfall of its world historical influence

A conserved target site in HIV-1 Gag RNA is accessible to inhibition by both an HDV ribozyme and a short hairpin RNA

Abstract: Antisense-based molecules targeting HIV-1 RNA have the potential to be used as part of gene or drug therapy to treat HIV-1 infection. In this study, HIV-1 RNA was screened to identify more conserved and accessible target sites for ribozymes based on the hepatitis delta virus motif. Using a quantitative screen for effects on HIV-1 production, we identified a ribozyme targeting a highly conserved site in the Gag coding sequence with improved inhibitory potential compared to our previously described candidates targeting the overlapping Tat/Rev coding sequence. We also demonstrate that this target site is highly accessible to short hairpin directed RNA interference, suggesting that it may be available for the binding of antisense RNAs with different modes of action. We provide evidence that this target site is structurally conserved in diverse viral strains and that it is sufficiently different from the human transcriptome to limit off-target effects from antisense therapies. We also show that the modified hepatitis delta virus ribozyme is more sensitive to a mismatch in its target site compared to the short hairpin RNA. Overall, our results validate the potential of a new target site in HIV-1 RNA to be used for the development of antisense therapies

Investigating a New Generation of Ribozymes in Order to Target HCV

For a long time nucleic acid-based approaches directed towards controlling the propagation of Hepatitis C Virus (HCV) have been considered to possess high potential. Towards this end, ribozymes (i.e. RNA enzymes) that specifically recognize and subsequently catalyze the cleavage of their RNA substrate present an attractive molecular tool. Here, the unique properties of a new generation of ribozymes are taken advantage of in order to develop an efficient and durable ribozyme-based technology with which to target HCV (+) RNA strands. These ribozymes resulted from the coupling of a specific on/off adaptor (SOFA) to the ribozyme domain derived from the Hepatitis Delta Virus (HDV). The former switches cleavage activity “on” solely in the presence of the desired RNA substrate, while the latter was the first catalytic RNA reported to function naturally in human cells, specifically in hepatocytes. In order to maximize the chances for success, a step-by-step approach was used for both the design and the selection of the ribozymes. This approach included the use of both bioinformatics and biochemical methods for the identification of the sites possessing the greatest potential for targeting, and the subsequent in vitro testing of the cleavage activities of the corresponding SOFA-HDV ribozymes. These efforts led to a significant improvement in the ribozymes' designs. The ability of the resulting SOFA-HDV ribozymes to inhibit HCV replication was further examined using a luciferase-based replicon. Although some of the ribozymes exhibited high levels of cleavage activity in vitro, none appears to be a potential long term inhibitor in cellulo. Analysis of recent discoveries in the cellular biology of HCV might explain this failure, as well as provide some ideas on the potential limits of using nucleic acid-based drugs to control the propagation of HCV. Finally, the above conclusions received support from experiments performed using a collection of SOFA-HDV ribozymes directed against HCV (−) strands

Serine protease inhibitors serpina1 and serpina3 are down-regulated in bone marrow during hematopoietic progenitor mobilization

Mobilization of hematopoietic progenitor cells into the blood involves a massive release of neutrophil serine proteases in the bone marrow. We hypothesize that the activity of these neutrophil serine proteases is regulated by the expression of naturally occurring inhibitors (serpina1 and serpina3) produced locally within the bone marrow. We found that serpina1 and serpina3 were transcribed in the bone marrow by many different hematopoietic cell populations and that a strong reduction in expression occurred both at the protein and mRNA levels during mobilization induced by granulocyte colony-stimulating factor or chemotherapy. This decreased expression was restricted to the bone marrow as serpina1 expression was maintained in the liver, leading to no change in plasma concentrations during mobilization. The down-regulation of serpina1 and serpina3 during mobilization may contribute to a shift in the balance between serine proteases and their inhibitors, and an accumulation of active neutrophil serine proteases in bone marrow extravascular fluids that cleave and inactivate molecules essential to the retention of hematopoietic progenitor cells within the bone marrow. These data suggest an unexpected role for serpina1 and serpina3 in regulating the bone marrow hematopoietic microenvironment as well as influencing the migratory behavior of hematopoietic precursors

Improved resolution and signal-to-noise ratio in laser-ultrasonics by SAFT processing.

Laser-ultrasonics is an emerging nondestructive technique using lasers for the generation and detection of ultrasound which presents numerous advantages for industrial inspection. In this paper, the problem of detection by laser-ultrasonics of small defects within a material is addressed. Experimental results obtained with laser-ultrasonics are processed using the Synthetic Aperture Focusing Technique (SAFT), yielding improved flaw detectability and spatial resolution. Experiments have been performed on an aluminum sample with a contoured back surface and two flat-bottom holes. Practical interest of coupling SAFT to laser-ultrasonics is also discussed

Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) Regulates Hematopoiesis and Bone Formation In Vivo

Background: Tissue inhibitor of metalloproteinases-3 (TIMP-3) inhibits matrix metalloproteinases and membrane-bound sheddases. TIMP-3 is associated with the extracellular matrix and is expressed in highly remodeling tissues. TIMP-3 function in the hematopoietic system is unknown

BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs

<p>Abstract</p> <p>Background</p> <p>Axolotls have the unique ability, among vertebrates, to perfectly regenerate complex body parts, such as limbs, after amputation. In addition, axolotls pattern developing and regenerating autopods from the anterior to posterior axis instead of posterior to anterior like all tetrapods studied to date. Sonic hedgehog is important in establishing this anterior-posterior axis of limbs in all tetrapods including axolotls. Interestingly, its expression is conserved (to the posterior side of limb buds and blastemas) in axolotl limbs as in other tetrapods. It has been suggested that <it>BMP-2 </it>may be the secondary mediator of sonic hedgehog, although there is mounting evidence to the contrary in mice. Since <it>BMP-2 </it>expression is on the anterior portion of developing and regenerating limbs prior to digit patterning, opposite to the expression of sonic hedgehog, we examined whether <it>BMP-2 </it>expression was dependent on sonic hedgehog signaling and whether it affects patterning of the autopod during regeneration.</p> <p>Results</p> <p>The expression of <it>BMP-2 </it>and <it>SOX-9 </it>in developing and regenerating axolotl limbs corresponded to the first digits forming in the anterior portion of the autopods. The inhibition of sonic hedgehog signaling with cyclopamine caused hypomorphic limbs (during development and regeneration) but did not affect the expression of <it>BMP-2 </it>and <it>SOX-9</it>. Overexpression of <it>BMP-2 </it>in regenerating limbs caused a loss of digits. Overexpression of <it>Noggin </it>(<it>BMP </it>inhibitor) in regenerating limbs also resulted in a loss of digits. Histological analysis indicated that the loss due to <it>BMP-2 </it>overexpression was the result of increased cell condensation and apoptosis while the loss caused by <it>Noggin </it>was due to a decrease in cell division.</p> <p>Conclusion</p> <p>The expression of <it>BMP-2 </it>and its target <it>SOX-9 </it>was independent of sonic hedgehog signaling in developing and regenerating limbs. Their expression correlated with chondrogenesis and the appearance of skeletal elements has described in other tetrapods. Overexpression of <it>BMP-2 </it>did not cause the formation of extra digits, which is consistent with the hypothesis that it is not the secondary signal of sonic hedgehog. However, it did cause the formation of hypomorphic limbs as a result of increased cellular condensation and apoptosis. Taken together, these results suggest that <it>BMP-2 </it>does not have a direct role in patterning regenerating limbs but may be important to trigger condensation prior to ossification and to mediate apoptosis.</p

A Modern Mode of Activation for Nucleic Acid Enzymes

Through evolution, enzymes have developed subtle modes of activation in order to ensure the sufficiently high substrate specificity required by modern cellular metabolism. One of these modes is the use of a target-dependent module (i.e. a docking domain) such as those found in signalling kinases. Upon the binding of the target to a docking domain, the substrate is positioned within the catalytic site. The prodomain acts as a target-dependent module switching the kinase from an off state to an on state. As compared to the allosteric mode of activation, there is no need for the presence of a third partner. None of the ribozymes discovered to date have such a mode of activation, nor does any other known RNA. Starting from a specific on/off adaptor for the hepatitis delta virus ribozyme, that differs but has a mechanism reminiscent of this signalling kinase, we have adapted this mode of activation, using the techniques of molecular engineering, to both catalytic RNAs and DNAs exhibiting various activities. Specifically, we adapted three cleaving ribozymes (hepatitis delta virus, hammerhead and hairpin ribozymes), a cleaving 10-23 deoxyribozyme, a ligating hairpin ribozyme and an artificially selected capping ribozyme. In each case, there was a significant gain in terms of substrate specificity. Even if this mode of control is unreported for natural catalytic nucleic acids, its use needs not be limited to proteinous enzymes. We suggest that the complexity of the modern cellular metabolism might have been an important selective pressure in this evolutionary process